DESCRIPTION: The illegitimate use of a bacterial pathogen is most likely and damaging with an agent that is readily dispersed and infectious by aerosol, stable in the environment after release, and capable of causing panic and debilitation of those affected. Coxiella burnetii fulfills all these criteria yet public health response to this agent, including vaccine intervention, is underdeveloped. The agent causes acute Q fever, occasional chronic disease, and very recently was linked to chronic vascular disease. Subunit immunogens that can provide protection against acute and chronic diseases without an adverse response are uncharacterized. The long-range goal of this project is to develop an effective subunit vaccine to provide immunity to individuals that are at risk of infection with C. burnetii. The central hypothesis is that outer membrane proteins can be used to develop protective immunity against Q fever. This will be accomplished by pursuing three specific aims. First, several major immunogenic outer membrane antigens will be identified and characterized. Two immunogenic outer membrane antigens, P-1 and Omp47, have been cloned by our group. Additional outer membrane proteins will be evaluated for reactivity with immune sera and major antigens cloned. This will include components of a putative type 4 secretion system. Next, the vaccinogenic potential of immunogenic outer membrane proteins will be evaluated. Mice will be vaccinated with recombinant protein in adjuvant and then challenged with a lethal dose of virulent C. burnetii. Alternatively, immunity to selected antigens will be developed by DNA vaccination and evaluated for the ability to protect against lethal challenge. Protective immunogens will also be evaluated in a guinea pig fever model infected through intraperitoneal and aerosol challenges. Finally, the components of the immune response elicited with protective subunit antigens will be characterized. The working hypothesis is that both humoral and cell mediated immune responses will be required to confer protection against a lethal or fever-inducing challenge of C. burnetii. The immune profile of protected animals will be evaluated for antibody development, Thl and Th2 cytokine expression, and T cell responses. Recombinant immunodominant antigens could also be used to develop improved diagnostic tools.